AP1: Exploiting Microbial Diversity for Natural Product Discovery Project Summary/Abstract The primary objective of the proposed research is to discover new, small molecule drug candidates from marine microorganisms cultured from Fiji and the Solomon Islands. This objective will be facilitated through the continued development of a productive microbial drug discovery program at the University of the South Pacific. Bioassays targeting cancer, infectious disease, neurological disorders, and neglected tropical diseases will be used to guide the isolation of compounds relevant to these targets. The structures of new compounds will be solved using modern spectral analyses and produced in sufficient quantities for effective pre-clinical evaluation. The research will target chemically rich microbial taxa including the marine actinomycete genus Salinispora and explore the relationships between biotic diversity and natural product discovery. The research benefits from a wealth of genome sequence data that has been acquired through the Joint Genome Institutes Community Sequencing Program. Bioinformatic analyses will be used to prioritize strains for chemical evaluation and to establish relationships between secondary metabolite biosynthetic potential, taxonomy, and the habitats and locations from which the stains originate. This information will be used to develop more effective sampling strategies and to provide new insight into the extant biosynthetic potential of marine bacteria and the evolutionary processes that generate structural diversity. Genome mining approaches will be used to link molecules to the pathways responsible for their production and to facilitate discovery and de-replication. The web-based tool NaPDoS (Natural Product Domain Seeker), which simplifies the analysis of genes involved with secondary metabolite biosynthesis, will be further developed to include additional pathway types and reference sequences. New cultivation methods will be developed that mimic natural conditions and provide ecologically relevant stimuli in an effort to induce secondary metabolite production. These studies will be coupled with transcriptome analyses, which will be used to determine the effects of culture conditions on biosynthetic gene expression. Highly sensitive methods in mass spectrometry will be used to better visual the secondary metabolome and generate networks that can be used to recognize new molecules, de-replicate known compounds, and search for correlations between geographic origin, phylogeny, and secondary metabolite production. Extensive post-doctoral, graduate, and undergraduate training will be provided throughout the program including training for host country scientists. Ultimately, this program aims to develop improved methods for natural product discovery and apply these approaches to the microbial resources in Fiji and the Solomon Islands in an effort to discover new drug candidates to treat diseases relevant to the US and the host nations.